Clinical dilemmas in viral liver disease

Management of acute HBV
• An acute infection may last up to six months
(with or without symptoms) and infected
persons are able to pass the virus to others
during this stage.
• A patient will test positive for the hepatitis B virus
(HBsAg+), HBc-IgM, and possibly the HBe-
antigen.
• Safe sex practices and vaccination of close
household members should be recommended.

Management of acute HBV
• Because the majority of patients with acute
HBV resolve this infection spontaneously,
treatment with an oral anti-HBV agent is not
necessary.

Fulminant Hepatitis B
• The rationale for treatment of fulminant
hepatitis B with antiviral therapy is to improve
liver function and to prevent death or the
need for liver transplantation.
• However, the use of an oral anti-HBV agent is
not unreasonable to use in a patient who is
developing acute liver failure from severe
acute HBV.

• There are data to encourage the use of
lamivudine in fulminant HBV & in acute HBV
infection of immunosuppressed patients such as
transplant recipients, although the data remain
patchy.
• There is no evidence to show that lamivudine is
harmful in these settings, so clinicians may
choose to use lamivudine for patients with severe
acute hepatitis and in the immunosuppressed.

Poor prognostic criteria for severe acute
hepatitis and these allow stratiﬁcation of patients
into high- and low- risk groups.
• O’Grady: age > 40 years, jaundice to
encephalopathy time > 7 days, bilirubin > 17.65
mg/dL (300 mmol/L), prothrombin time > 50 s.
• Bernuau: age > 40 years, cerebral oedema,
bilirubin > 15 mg/dL (255 mmol/L), prothrombin
time > 25 s more than control.

• Lamivudine 100 mg daily for 3 months
• The value of agents other than lamivudine in
these settings remains untested and whether
the third-generation antivirals with enhanced
efﬁcacy and lower resistance proﬁles will
prove to be more effective remains to be
determined.

• There is thus evidence that lamivudine in
fulminant hepatitis B may improve outcomes,
but its use in all cases of acute hepatitis B
cannot be recommended.

Rethinking the inactive carrier state: management of patients
with low-replicative HBeAg-negative chronic hepatitis B and
normal liver enzymes

• Dynamic nature of the inactive carrier state with potential
for reversion to HBeAg-positive hepatitis, spontaneous loss
of HbsAg or, more frequently, reactivation to HBeAg-
negative chronic hepatitis.

• Serial HBV DNA testing has been shown to
improve the classiﬁcation of inactive disease
and accordingly some guidelines advocate
serial HBV DNA testing to ensure that the
inactive state is maintained and when ALT
elevations are noted or clinical suspicion of
reactivation is raised.

• Diagnosis of the inactive carrier state requires
repeated assessments of ALT and HBV DNA over at
least a 1-year period using the most stringent ALT cut-
offs (30 IU/mL in men, 19 IU/mL in women) to truly
differentiate from HBeAg-negative CHB.
• Lifelong serial monitoring for prompt diagnosis of
viral relapse and initiation of antiviral therapy for
individuals with progression to HBeAg-negative CHB
(HBV DNA > 2000 IU/mL, elevation in ALT and/or
active necroinﬂammatory histology on liver biopsy).

Liver biopsy
• Even when the data were reanalysed using the
updated norms for ALT (30 IU/mL for men, 19
IU/mL for women), ALT and HBV DNA were
inaccurate in distinguishing histologically
active and inactive disease.

Liver biopsy
• There is insufﬁcient evidence at this time to
recommend routine liver biopsy for low- replicative
chronic HBV infection, although it might be
considered histological evaluation for selected
individuals with risk factors for progression, such as :
• ALT or other laboratory parameters
• Imaging suggesting progressive disease,
• Closeness of HBV DNA to the cut-off of 2000 IU/Ml
• Male gender
• Asian ethnicity
• Age over 35
• Genotype C
• Presence of precore or basal core promoter
mutations

HBV genotype
• Determination of HBV genotype and
assessment for the presence of precore or
basal core promoter mutations may prove
useful for long-term surveillance.
• It has been shown that genotype C is
associated with increased risk of reactivation
to HBeAg-negative CHB and progression to
cirrhosis

HBV genotype
• Addition of the precore (A1896) and basal
core promoter (T1762/A1764) mutations into
treatment algorithms might assist in the
identiﬁcation of patients at risk for
developing HCC

• Given the small but signiﬁcant risk of
progressive liver disease, cirrhosis and
HCC, the term ‘inactive carrier state’
should be reconsidered and replaced
with ‘low- replicative HBeAg-negative
CHB’ for patients with low- level rather
than undetectable HBV DNA.

• Patients should be counselled on lifestyle
modiﬁcations, including abstinence from alcohol,
weight loss and glycaemic control where relevant.
• Seronegative individuals should be offered
vaccination against hepatitis A virus.
• The risk of transmission should be routinely
discussed, and family members and household
contacts should be vaccinated against HBV, if not
already immune, even if the index patient is HBV
negative.

• Patients in the inactive carrier state should be
counselled on the risk of reactivation in the
face of immunosuppression (chemotherapy,
systemic steroids, anti-TNF-a treatments) and
appropriate prophylactic antiviral therapy
should be administered.

HBeAg-negative chronic hepatitis B infection with
abnormal transaminases and minimal changes on liver
biopsy

• However, many patients with HBeAg-negative
disease present with moderately high levels
of HBV DNA, ﬂuctuating mildly deranged liver
function tests and minimal changes on liver
biopsy.
• The most appropriate management of
such patients is unclear.
HBeAg-negative chronic hepatitis B infection with
abnormal transaminases and minimal changes on liver
biopsy

The case for early therapy
• The data from cohort studies indicate that persisting
medium- to high-level viraemia in patients with
HBeAg- negative HBV is associated with an increased
risk of liver disease.
• Since studies of antiviral therapy have shown that
therapy may improve liver histology and reduce the
risk of developing complications in patients with
severe disease, it seems reasonable to presume that
therapy in patients with persisting viraemia and
minimal liver damage will confer long-term beneﬁts.

• If patients with minimal histological disease are
not offered antiviral therapy, the risks of disease
progression are such that long-term follow-up
with regular monitoring of liver function tests and
viral load is required.
• Most physicians would agree that liver biopsy
should be repeated at regular intervals (perhaps
every few years) and therefore avoiding therapy
requires extensive follow-up with regular
histological assessment.

• Thus it can be argued that early therapy for
patients with minimal histological damage :
- Reduces the risk of long-term liver damage,
and even risk of HCC
- Avoids repeat liver biopsy assessment
- Facilitates compliance
- Potentially reducing the risk of inadvertent
transmission.

The case for delaying therapy
• Therapy in minimal disease requires a long-
term commitment by the patient to take
medication regularly and undergo frequent
monitoring.
• For patients who choose to take interferon-
based therapies, the side effects may be
considerable

• for patients who choose oral antiviral agents,
regular review with repeated blood tests over
many years is required.
• For patients who choose to take oral antiviral
agents there is a risk that in the long term
drug-resistant mutations will emerge and
reduce the efﬁcacy of therapy.

• Although the oral drugs that are currently
available to treat patients with HBV (e.g.
entecavir and tenofovir) have an excellent
safety record in the short term, their long-
term safety in patients with HBV has not
been determined and their effects on the
developing fetus are currently unknown
although the available data does not give rise
to any concerns.

• Thus treating patients with minimal disease
exposes them to therapy with no proven
beneﬁts and an unknown risk of long-term
complications, including viral resistance.

Expert opinion
• Two international groups have recently
compiled guidelines for the management of
chronic HBV infection
• In view of the lack of high-quality evidence
relating to the management of patients with
minimal histological disease, it is not
surprising to ﬁnd that the two groups have
reached slightly different conclusions.

Guidelines
• American Association for the Study of Liver
Diseases (AASLD) : suggest that ‘These patients
generally should not be initiated on treatment
but a liver biopsy may be considered in patients
with fluctuating or minimally elevated ALT
levels, especially in those aged over 40 years of
age’. The guidelines suggest that ‘treatment may
be initiated if there is moderate or severe
necroinflammation or significant fibrosis on liver
biopsy’.

• The European guidelines adopt a subtly
different approach, recommending that :
‘patients with slightly elevated ALT (less than
2 times ULN) and mild histological lesions
(less than A2F2 with METAVIR scoring) may
not require therapy.
• Follow-up is mandatory’.
Guidelines

Suggestions for management
• I usually advise young fertile women who are
considering starting a family to defer therapy but
to continue to undergo regular monitoring.
• For patients with a family history of liver disease,
particularly those with a history of liver cancer, I
usually advocate early therapy.
• For patients who have other risk factors for
progressive disease (e.g. men over the age of 40)
early therapy is probably the most appropriate
option .

• Patients who have no risk factors that
predispose them to advanced liver disease a
policy of careful observation is appropriate,
provided that the patient is willing to
consider regular liver biopsies to monitor
disease progression.
Suggestions for management

Hepatitis B infection in surgeons
and healthcare workers: what
should we do to protect
patients?

• A 28-year-old surgery resident, native of Nigeria,
comes to you because he has a prior history of
hepatitis B infection, acquired perinatally. He had
a liver biopsy 6 months ago showing minimal
inflammation and no fibrosis. He is applying for
privileges at another hospital and is concerned
about his HBV infection and the implications for
his ability to practice.
Laboratory Data:
ALT – 13 IU/dL (normal = 10-40)
AST - 12 IU/dL (normal = 10-35)
Albumin – 4.1 g/dL (normal = 3.5 – 4.9)
Total bilirubin – 0.4 mg/dL (normal = 0.1-1.2)
HBsAG (+)
HBV-DNA – 45 million IU/dL
HBeAG – (+)
HBeAB – (-)
Your advice to this patient should be:

Your advice to this patient should be:
• A. Do not treat, he is in the immune tolerant phase
• B. Tell him not to worry, as long as he uses double
gloves and universal precautions, he should be ok.
• C. Discuss the risks of transmission to his patients and
recommend antiviral therapy
• D. Increase surveillance interval for HCC to every 3
months
• E. Tell the patient that he will not be able to practice
surgery as long as he is HBsAg (+)
Hepatitis B infection in surgeons and
healthcare workers: what should we do to
protect patients?

Explanation C
• This patient is in the immune tolerant
stage of the disease and has minimal
inflammation on liver biopsy and normal
ALT. Under normal circumstances,
antiviral therapy would not be
recommended. However, recent
guidelines suggest that healthcare workers
with chronic HBV and a viral load >10,000
copies cannot perform surgery or invasive
procedures due to the risk of transmission
to others.

• Finally, option E is incorrect as he will be able
to perform surgery if the viral load is <10,000
copies, whether spontaneously or treatment
induced, regardless of the HBsAG status.
protect patients?

protect patients?

• The risks of transmission are inevitably
greater in those who perform
prolonged, open surgical procedures
but healthcare workers who take part
in any invasive procedure may also
pose a risk to their patients.
protect patients?

• Definition of a high-risk procedure is not
universally agreed:
- UK the definition of an ‘exposure-prone
procedure’ is one in which the operator’s hands
are in a body cavity with a sharp instrument.
- This definition includes surgical operations,
dental procedures and obstetric interventions but
does not include endoscopic procedures
or venesection.
protect patients?

• Healthcare workers with HBeAg-negative HBV
may also transmit the virus to patients,
particularly if the healthcare worker has high-
level viraemia .
• The level of viraemia deemed ‘safe’ varies from
country to country but in the UK a value of less
than 103 genome equivalent per ml is regarded
as safe and healthcare workers with viral loads
below this level are permitted to operate freely.
• Other countries have adopted slightly higher viral
loads.
protect patients?

• The UK has one of the most rigorous policies
and current UK policy is to allow infected
healthcare workers to perform exposure-
prone procedures only if their pretreatment
viral load is low (< 105 genome equivalents
per mL) and only if they are undergoing
therapy that is carefully monitored by a
named physician.
protect patients?

• You are asked to see a 29-year-old Cambodian
woman who is currently in the first trimester of her
first pregnancy because she tested positive for
hepatitis B virus. She immigrated to the United
States at the age of 16 and this is the first ...time she
was told she had HBV. She feels well. Her physicial
examination is unremarkable for a women in her
third month of pregnancy. The following laboratory
studies were obtained: AST 11 IU/L (normal 35-48),
ALT 12 IU/L (normal 38-45), ALP 99 IU/L (normal 80-
120), Bilirubin 0.3 mg/dl (normal 0.4-1.1), Albumin
4.1 gm/dl (normal 3.4-5.1). HBsurface antigen
positive, anti-HBcore positive, anti-HBsurface
negative, anti-HB e-antigen negative, HBe antigen
positive , HBV DNA 50,000 IU/ml.
Which of the following would you recommend?

Management of hepatitis B virus
infection in pregnancy
Which of the following would you recommend?
A. Initiate treatment with either entecavir or
tenofovir
B. Perform an alpha-feto protein to screen for
liver cancer
C. Vaccinate the child within 12 hours of birth
with HB vaccine
D. Re-evaluate the patient for treatment after
she delivers the child

Explanation D
• Women with chronic HBV are at risk to transmit
vertically to the newborn. This risk can be
significantly reduced when the child is vaccinated
with HBIG and HB vaccine within 12 hours of
birth and HB vaccine is administered 1 and 5
months thereafter. The combination of HBIG and
HB vaccine is effective in preventing vertical
transmission of HBV in about 85-90% of cases.

• The greatest risk for the baby acquiring HBV
vertically from the mother despite receiving HBIG
and HB vaccine is when the mother has an HBV
DNA level of 10,000,000 IU/ml or greater. It is
therefore recommended that women with serum
HBV DNA of 10,000,000 IU/ml receive anti-viral
therapy during the third trimester of the
pregnancy. A recent placebo controlled study has
demonstrated that treatment of women with
serum HBV DNA of greater than 1,000,000 IU/ml
during the third trimester of the pregnancy with
telbivudine and continuing this medication for
one month after delivery reduced the risk of
vertical transmission from 15% to 0.

Management of hepatitis B virus infection in pregnancy

• Mother-to-child (vertical) transmission of
hepatitis B virus (HBV) accounts for
approximately 35–40% of chronic infections
worldwide
• Vertical transmission can occur in the prenatal
period, during delivery or early after birth,
although most transmissions occur during
labour and delivery.
Management of hepatitis B virus infection
in pregnancy

• If the mother is HBeAg positive and no
immunoprophylaxis is given, more than 85%
of offspring will become chronically infected
with HBV .
• If the mother is anti- HBe positive and no
immunoprophylaxis is given, less than 5% of
offspring become chronically infected with
HBV .
Management of the HBsAg-positive
pregnant woman

• Children of anti-HBe-positive mothers are also
at risk of acute and fulminant HBV infection
which, while rare, has a mortality rate of up
to 75% .
• Passive–active immunization administered to
infants of HBeAg-positive women results in
vertical transmission being reduced from 90%
to between 1.1-15% with a signiﬁcantly
reduced risk of acute and fulminant hepatitis
pregnant woman

HBV DNA level determines
consideration of antiviral treatment
• Lamivudine taken in the third trimester (34
weeks’ gestation ) by mothers with a high viral
load reduces vertical transmission further than
that achieved by passive–active immunization of
the infant alone, but does not prevent all cases .
• TDF and LdT are listed as pregnancy category B
drugs .
• LAM, whereas ADV and ETV as category C drugs.

• Because of evidence of an increased risk of
chronic carriage in infants of HBeAg-positive
women with a high HBV DNA level, we
recommend that a conservative approach is
taken in the rare case of an anti-HBe-positive
women.
• As exacerbations of chronic hepatitis B may
occur, women with HBV should be monitored
closely after delivery.
pregnant woman

• Some 1% of HBsAg-positive mothers
are both HBeAg and anti-HBe
negative
• Currently, it is recommended to treat
them in the same way as mothers
who are HBeAg positive.
Management of pregnant women
who lack E-markers

• Recombivax HB and Engerix-B, are administered
in typical doses that contain 10–40 mg/mL of the
HBsAg protein.
• With administration of the three-aliquot series,
the accepted protective serum antibody level is
deﬁned as a detectable titre of 10 mIU/mL (or
10 IU/L) or greater.
• Seroconversion with protective serum titres of
anti-HBs is achieved in 90–95% of healthy
individuals after completion of the vaccination
series .
High-risk needle exposure in hepatitis B
vaccine failures: what are the options?

• Non-response is deﬁned as an anti-hepatitis B
surface antigen (anti-HBs) titre below 10
mIU/mL, typically measured 1–6 months after
the last dose of a full immunization schedule.
• Hyporesponse is deﬁned as an anti-HBs titre
greater than 10 and less than 99 mIU/mL.
• Predictors of non-response include age 30 years,
male gender, obesity, tobacco use, alcoholism,
diabetes, chronic renal disease, chronic liver
disease and immunocompromised states (such as
HIV or medication-induced immunomodulation) .
HBV vaccination and characteristics of
failure

• The true non-responder is not protected against HBV
infection if exposure occurs.
• The CDC recommends revaccination of non-
responders with one or more additional vaccine doses.
• In the case of three or more additional booster
injections, as many as 30–50% of recipients respond
with appropriate production
• For individuals with risk factors for non-response,
some clinicians also advocate using higher doses of
vaccine, speciﬁcally 40-mg dosing for the initial three
injections instead of the standard adult dosing of 10–
20 mg
HBV vaccination and characteristics of
failure

High-risk needle exposure in hepatitis B
vaccine failures: what are the options?

Antiviral prophylactic treatment of chronic hepatitis B to
prevent viral reactivation during cytotoxic chemotherapy

• HBV reactivation is defined as :
An abrupt increase in HBV replication
manifesting as a rapid increase in
serum HBV DNA level or detection of
HBsAg in a person who was previously
HBsAg negative and anti-HBc positive.
Antiviral prophylactic treatment of chronic hepatitis B
to prevent viral reactivation during cytotoxic
chemotherapy

• Cases have also been reported in patients who
are :
• HBsAg negative, but test positive for
hepatitis B core antibody (anti-HBc).
• Patients who appear to have resolved
hepatitis B infection (i.e., HBsAg
negative, anti-HBc positive, and hepatitis
B surface antibody [anti-HBs] positive).
chemotherapy

• Screen all patients for HBV infection
before initiating treatment with
Arzerra or Rituxan by measuring
HBsAg and anti-HBc.
• Note that patients who have protective
antibodies due to immunization will
test positive only for anti-HBs.
chemotherapy

• For patients who show evidence of prior HBV
exposure by testing positive for HBsAg or anti-
HBc, consult with physicians with expertise in
managing hepatitis B regarding monitoring and
consideration for HBV antiviral therapy.
• Monitor patients with evidence of prior HBV
infection for clinical and laboratory signs of
hepatitis or HBV reactivation during and for
several months following Arzerra or Rituxan
therapy.
chemotherapy

• It is suggested that clinicians administer
prophylactic treatment with lamivudine or other
antiviral agents prior to chemotherapy to reduce
the risk of viral reactivation in HBV carriers.
• Full serological work-up for HBV markers is
recommended for all at-risk patients prior to
chemotherapy, especially those from highly endemic
regions.
• Prophylactic treatment is recommended for those
testing positive for HBsAg and risk assessment
should be performed on HBsAg-negative patients.
chemotherapy

• We recommend initiating anti-HBV treatment at
least 1 week before the beginning of
chemotherapy.
• The duration of treatment is not yet clearly
established but reasonable guidelines are as
follows: a minimum of 6 months after cessation
of conventional chemotherapy
• 12 months or longer for patients with high pre-
chemotherapy HBV DNA levels or
immunosuppression regimens involving
monoclonal antibodies such as rituximab.
chemotherapy

Clinical dilemmas in viral liver disease

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